Thymidine is an effective rescue agent for high dose methotrexate in man that may provide much more selective rescue than leucovorin. The present research proposal is aimed at investigating the ability of thymidine rescue to improve the therapeutic ratio of methotrexate. Included in this program are studies of the major factors that control the selectivity of thymidine rescue, and studies of the metabolic basis for thymidine rescue selectivity. These studies will be carried out using human tumors growing in nude mice, a system that permits experimental modulation of the factors most likely to be of significance to the selectivity of thymidine rescue. The results of these studies will be used to guide ongoing clinical evaluation of high dose methotrexate with thymidine rescue.